Overcoming the obstacles of eliciting broadly neutralizing antibodies (NAb) to HIV-1 will be a major step forward to developing a successful AIDS vaccine. The long-term objectives of project 2 are to design, evaluate and select novel HIV-1 enveloped based immunogens which are capable of inducing broad neutralizing antibodies which will have a protective effect in vaccinated individuals. The challenge and reason for this B-cell epitope focused approach is that HIV-1 has developed multiple mechanisms to shield itself and evade the antiviral effects of many antibodies. By far most host antibodies directed to the envelope (Env) of HIV-1 are ineffective in eliciting broad Nab responses. There are however several conserved B-cell epitopes which are rarely exposed, but when recognized by the host are able to elicit a broad Nab response. Here we aim to develop vaccine immunogens which together will focus the antibody response to highly conserved Env epitopes. Specifically our aims are to: 1. To improve the presentation of conformational Nab B-cell epitopes (mimotopes) for optimal presentation in vivo by;a) Combinatorial Synthesis and "Click" chemistry through direct collaboration and interaction with Core D, and, b) Engineered virus-like particles (VLPs) expressing Nab epitopes. Experience in VLPs expressing HIV peptides will include p55 Gag as well as Hepatitis B particles (Univ Regensburg, this project). 2. To identify the optimal vaccine platforms (protein, peptide, and/or viral vector) and regimen for either priming or boosting conformationaly dependent epitope specificities. This will be facilitated by close interaction with the vaccine technologies core (B) as well as complementary Env structures developed in projects 1 and 3. 3. To determine how many Nab peptide epitopes can optimally be combined in a prime boost immunization protocol to ultimately generate robust neutralizing antibody responses in an outbred population, evaluated first in rabbits and subsequently more stringently in non-human-primates models (Core C). 4. To determine "proof of principle" protective efficacy of these optimized mimotope-based vaccine regimens in the SHIV rhesus macaque vaccine challenge model. The best combination of NAb B-cell epitope presenting structures and delivery systems will be revealed in heterologous and mucosal challenge studies.